19-Hydroxy-19-methyl-inter-phenylene-13,14-dihydro-PG1 compounds

ABSTRACT

The present invention provides novel 19-hydroxy-19-methyl-inter-phenylene-13,14-dihydro-PG 1  compounds, methods for their preparation and pharmacological use for the induction of prostaglandin-like effect.

DESCRIPTION CROSS REFERENCE TO RELATED APPLICATIONS

The present application is a division of Ser. No. 025,878, filed April2, 1979, now abandoned.

BACKGROUND OF THE INVENTION

The present invention relates to novel prostaglandin analogs.Particularly, these compounds are analogs of the prostaglandins whereinthe C-19 position is substituted by hydroxy, i.e.,19-hydroxy-19-methyl-PG compounds. Most particularly, the presentinvention relates to novel19-hydroxy-19-methyl-inter-phenylene-13,14-dihydro-PG₁ compounds, adisclosure of the preparation and use of which is incorporated here byreference from U.S. Pat. No. 4,228,104.

PRIOR ART

Prostaglandin analogs exhibiting hydroxylation in the 19-position areknown in the art. See, for example, U.S. Pat. No. 4,127,612, Sih, J. C.,Prostaglandins 13:831 (1977) and U.S. Pat. Nos. 3,657,316, 3,878,046,and 3,922,297. See also the additional references cited in U.S. Ser. No.025,878.

SUMMARY OF THE INVENTION

The present invention particularly provides:

a compound of the formula ##STR1##wherein D is (1) --(m--Ph)--(CH₂)₂ --,or

(2) --(m--Ph)--O--CH₂ --,

wherein --(m-Ph)-- is inter-meta-phenylene, and

wherein Q is α--OH:β--R₅ or α--R₅ :β--OH, wherein R₅ is hydrogen ormethyl;

wherein R₆ is

(a) hydrogen,

(b) alkyl of one to 12 carbon atoms, inclusive,

(c) cycloalkyl of 3 to 10 carbon atoms, inclusive,

(d) aralkyl of 7 to 12 carbon atoms, inclusive,

(e) phenyl,

(f) phenyl substituted with one, 2, or 3 chloro or alkyl groups of oneto 3carbon atoms, inclusive,

(g) --(p--Ph)--CO--CH₃,

(h) --(p--Ph)--NH--CO--(p--Ph)--NH--CO--CH₃,

(i) --(p--Ph)--NH--CO--(p--Ph),

(j) --(p--Ph)--NH--CO--CH₃,

(k) --(p--Ph)--NH--CO--NH₂,

(l) --(p--Ph)--CH═N--NH--CO--NH₂,

(m) β-naphthyl,

(n) --CH₂ --CO--R₂₈,

wherein (p--Ph) is para-phenyl or inter-para-phenylene, wherein R₂₈isphenyl, p-bromophenyl, p-biphenylyl, p-nitrophenyl, p-benzamidophenyl,or 2-naphthyl, or

(o) a pharmacologically acceptable cation;

wherein R₂ is hydrogen, hydroxyl, or hydroxymethyl;

wherein R₃ and R₄ are hydrogen, methyl, or fluoro, being the sameordifferent, with the proviso that one of R₃ and R₄ is fluoro only whenthe other is hydrogen or fluoro;

wherein W is oxo, methylene, α--OH:β--H, or α--H:β--OH; and

wherein X is --CH₂ CH₂ --.

With regard to the divalent the substituents described above (e.g., Q)these divalent radicals are defined as α--R_(i) :β--R_(j), wherein R_(i)represents the substituent of the divalent moiety in the alphaconfiguration with respect to the ring and R_(j) represents thesubstituent of the divalent moiety in the beta configuration withrespect to the plane of the ring. Accordingly, when Q is defined asa--OH:β--R₅, the hydroxy of the Q moiety is in the alpha configuration,i.e., as in the natural prostaglandin, and the R₅ substituent is in thebeta configuration.

Specific embodiments of the present invention include:

19-hydroxy-19-methyl-3,7-inter-m-phenylene-13,14-dihydro-PGF₁ α.

The compounds of the present invention are particularly useful forinducingprostaglandin-like biological effects, and is described in U.S.Ser. No. 025,878. Uses of compounds in accordance with the presentinvention include, therefore, anti-asthmatic indications.

I claim:
 1. A compound of the formula ##STR2## wherein D is (1)--(m--Ph)--(CH₂)₂ --, or(2) --(m--Ph)--O--CH₂ --,wherein --(m--Ph)-- isinter-meta-phenylene, and wherein Q is α--OH:β--R₅ or α--R₅ :β--OH,wherein R₅ is hydrogen or methyl; wherein R₆ is (a) hydrogen, (b) alkylof one to 12 carbon atoms, inclusive, (c) cycloalkyl of 3 to 10 carbonatoms, inclusive, (d) aralkyl or 7 to 12 carbon atoms, inclusive, (e)phenyl, (f) phenyl substituted with one, 2, or 3 chloro or alkyl groupsof one to 3 carbon atoms, inclusive, (g) --(p--Ph)--CO--CH₃, (h)--(p--Ph)--NH--CO--(p--Ph)--NH--CO--CH₃, (i) --(p--Ph)--NH--CO--(p--Ph),(j) --(p--Ph)--NH--CO--CH₃, (k) --(p--Ph)--NH--CO--NH₂, (l)--(p--Ph)--CH═N--NH--CO--NH₂, (m) β-naphthyl, (n) --CH₂--CO--R₂₈,wherein (p--Ph) is para-phenyl or inter-para-phenylene,wherein R₂₈ is phenyl, p-bromophenyl, p-biphenylyl, p-nitrophenyl,p-benzamidophenyl, or 2-naphthyl, or (o) a pharmacologically acceptablecation; wherein R₂ is hydrogen, hydroxyl, or hydroxymethyl;wherein R₃and R₄ are hydrogen, methyl, or fluoro, being the same or different,with the proviso that one of R₃ and R₄ is fluoro only when the other ishydrogen or fluoro; wherein W is oxo, methylene, α--OH:β--H, orα--H:β--OH; and wherein X is --CH₂ CH₂ --. 2.19-Hydroxy-19-methyl-3,7-inter-m-phenylene-13,14-dihydro-PGF₁ α, acompound according to claim 1.